What’s next with AX-158?

While we wait for the data in psoriasis patients with our lead program AX-158 (expected before year end), many are asking us what potential new indications there could be for this asset. One of the very exciting aspects of Nck modulation is that it has a very broad potential applicability.

At Artax Biopharma we are working on a completely new approach to treating a broad range of autoimmune diseases, one which is aimed at achieving immunomodulation without immune suppression. The T cell receptor (or TCR) is central to healthy T cell function and a well-functioning immune system. In early development, T cells that activate to self are clonally deleted which allows the immune system to distinguish self from foreign antigens. When clonal populations of T cells develop that have too high an avidity for self-antigens (through the TCR), T cells behave abnormally, attacking a patient’s own tissues and organs. This results in autoimmune diseases in which T cells activate and cytokine production results, driving symptoms. Nck is an adaptor protein which plays a direct role in regulating T cell responses. Nck binds to the activated TCR, amplifying weak TCR signaling and contributing to erroneous activation.

We have built a convincing data package demonstrating the mode of action, activity, and tolerability of our lead asset, AX-158. This first-in-class Nck modulator has shown strong cytokine modulation of healthy donor PBMC’s following TCR stimulation as well as modulation of mixed lymphocyte reaction responses. We saw therapeutic efficacy in murine models of self-antigen activation (EAE), with a prolonged pharmacodynamic effect in EAE, suggesting durable immune modulation. There was also discrimination of neo-antigen and self-antigen in an immune/oncology model, as well as a lack of immunosuppression supported by data in models of strong antigen stimulation, which was very exciting for us to see.

We have been highly encouraged by observations of efficacy in dermal models of immune activation, as well as in multiple other models in T cell mediated autoimmune diseases, supporting the potentially broad application of Nck modulators. We have seen strong preclinical evidence of activity in the Th2, Th17, Th1/Th0 cells, suggesting that applications could be quite broad across the autoimmune space. As a final example, we have observed AX-158 modulating cytokine responses in PBMCs from atopic dermatitis patients in response to house dust mites (HDMs), illustrating the relevance of the mechanism to weak avidity antigen activation beyond self. Therefore, we see atopic dermatitis as a key next indication, building on the experience gained with psoriasis patients.

-Dr. Christopher VanDeusen CSO